Non-insulin-dependent diabetes mellitus (NIDDM), type II diabetes, is one of the most common diseases in the elderly population of the USA, and is especially common among minority population. NIDDM is caused by (1) impaired insulin secretion from islets of Langerhans in the pancreas, and (2) impaired sensitivity of peripheral tissues (such as muscle, fat, and liver) to insulin. A promising new approach for treatment of NIDDM is the use of incretin hormones such as glucagon-like peptide. Incretins have many desirable effects which may help NIDDM patients. Incretins stimulate insulin secretion and inhibit glucagon secretion. In addition we have found that GLP stimulates insulin action at insulin target tissues. For example, glucose uptake and lipid synthesis in cultured adipocytes is stimulated by GLP. We have found that GLP receptor mRNA is present in many different tissues from rat, further suggesting extrapancreatic effects in GLP. We have evidence that the GLP receptor cascade acts differently in pancreas versus extrapancreatic tissues. Our experiments will test whether different GLP receptor isoforms are present in pancreas versus extrapancreatic tissues or whether different signal transduction pathways are coupled to GLP receptor in different tissues. Further molecular cloning of GLP receptor isoforms and the study of signal transduction involved in GLP action will allow the development of new terapeutic agents for NIDDM.